Bile acids and oestrogen receptor activity in breast cancer

inhitor nordihydroguaiaretic acid (10-100p~) did not prevent the inhibition of histamine-stimulated secretion by EGF, and therefore prostaglandins are probably not involved in this action of EGF. Combination of histamine with histamine H,-receptors on the parietal cell membrane activates adenylate cyclase, and the associated rise in the concentration of cyclic AMP is thought to mediate the action of histamine in this cell type. Since EGF did not inhibit aminopyrine accumulation stimulated by 30, 56, 100 or 1000pM-dibutyryl cyclic AMP its action against histamine-stimulated secretion could involve an effect on the production or hydrolysis of cyclic AMP. Furthermore, since the inhibitory action of EGF against a range of concentrations of histamine was blocked by 0.1 m~-3-isobutyl-l-methylxanthine it seems possible that EGF could have been increasing cyclic AMP phosphodiesterase activity. However, 3-isobutyl-1-methylxanthine inhibits phosphodiesterases acting on both cyclic AMP and cyclic GMP, and can increase intracellular cyclic GMP in parietal cells (Heim & Ruoff, 1985). The action of dibutyryl cyclic GMP (0.1-1 .O mM) on the inhibitory action of EGF against histamine was therefore investigated. Dibutyryl cyclic GMP itself inhibited histamine-stimulated aminopyrine accumulation, and there was a lack of additivity between the inhibitory actions of dibutyryl cyclic G M P and EGF (Fig. I). This lack of additivity was not a consequence of the aminopyrine accumulation ratio in the presence of both agents being reduced to that found in unstimulated cells. The above results suggest a number of possibilities. First, cyclic GMP could block part of the signalling mechanism responsible for the inhibitory action of EGF, but that an agent which itself is an inhibitor should act in this fashion is perhaps somewhat unlikely. Secondly, cyclic GMP could mediate the action of EGF, and the effects of the two agents together would therefore be less than additive. Finally, cyclic GMP and EGF could act in parallel on the same effector system, and in this context it is interesting that certain cyclic AMP phosphodiesterases are activated by cyclic GMP (Houslay, 1986). In conclusion, the inhibition of histamine-stimulated secretory activity by EGF in parietal cells isolated from the rat does not seem to be mediated by prostaglandins, but the involvement of cyclic nucleotides, although indicated, remains to be clarified.